Coagulation is defined as a transformation of a liquid or sol into a soft, semi-solid or solid mass. Blood naturally coagulates to form a barrier when trauma or pathologic conditions cause vessel damage. There are two well-recognized coagulation pathways: the extrinsic or thromboplastin-controlled and the intrinsic or prothrombin/fibrinogen-controlled coagulation pathway. Both the extrinsic and intrinsic pathways result in the production of thrombin, a proteolytic enzyme that catalyzes the conversion of fibrinogen to fibrin.
Coagulation tests which measure a blood sample's ability to form a clot or coagulate have been developed and used to measure the Prothrombin Time (PT) of a blood sample. Such tests are commonly referred to as PT tests. PT tests find use in a number of different applications. For example, PT tests find use in monitoring patients undergoing anticoagulant therapy. Other situations where PT tests find use include tests to determine: acquired platelet function defect; congenital platelet function defects; congenital protein C or S deficiency; deep intracerebral hemorrhage; DIC (Disseminated intravascular coagulation); factor II deficiency; factor V deficiency; factor VII deficiency; factor X deficiency; hemolytic-uremic syndrome (HUS); hemophilia A; hemophilia B; hemorrhagic stroke; hepatic encephalopathy; hepatorenal syndrome; hypertensive intracerebral hemorrhage; idiopathic thrombocytopenic purpura (ITP); intracerebral hemorrhage; lobar intracerebral hemorrhage; placenta abruption; transient ischemic attack (TIA); Wilson's disease; and the like. As such, PT tests find use in a variety of different applications.
A number of different PT determination tests and devices have been developed. Such devices and test protocols include both optical based devices, such as those described in U.S. Pat. No. 6,084,660; to R. Shartle; and electrochemical based devices, such as those described in U.S. Pat. Nos. 6,046,051; 6,060,323 and 6,066,504; all to A. Jina. In this latter group of patents a device is disclosed which is suitable for electrochemical determination of a change of fluid viscosity in a sample, where the device is characterized by the presence of side-by-side electrodes. This configuration requires the use of relatively large volumes of sample and a measurement protocol that implements a time dependent deconvolution of the background response; i.e., a signal is measured over time and is then distinguished over background. Thus, the protocols employed with Jina's devices are more complicated and perhaps less robust than the protocols used in the present invention described below.
Furthermore, current point-of-care coagulation devices require relatively large samples of blood (≧20 microliters) to perform a PT assay. To obtain such a large volume of blood, use of a conventional lancet is required. However, the use of conventional lancets can cause pain and trauma to a user and potentially lead to improper compliance with an anticoagulant therapy.
While a number of different PT determination tests and devices have been developed, there continues to be a need for additional protocols and devices. Of particular interest would be the development of PT system that provided for rapid and accurate PT determinations with small sample volumes using inexpensive device components, such as disposable reagent strips. Of even greater interest would be the development of an electrochemical device and protocol that exhibits the above desirable parameters, is suitable for use with small sample volumes, produces minimal pain in a user, and can provide a simple-to-interpret signal that converges to a steady-state value.
Relevant Literature
United States Patent of interest include: U.S. Pat. Nos. 6,084,660; 6,066,504; 6,060,323; 6,046,051; 5,942,102; 5,916,522; 5,628,961; 5,554,531; and 5,300,779. Also of interest are WO 97/18465; WO 95/06868; EP 974840 and GB 1 299 363.